NO792696L - MENOCARBOXYLATES OF PHENYLGUANIDIC ACID ESTERS AND PROCEDURES FOR THEIR PREPARATION - Google Patents

Description

Monocarboxylates of phenylguanidine sulfonic acid esters, process for their preparation and their use as medicine.

It is known that phenylguanidines of formula:,

in which R means lower alkyl, R' means lower alkyl or hydrogen and R" means -C4Hg, -COCgH5, -OCgH5 or -SC6H5 are anthelminthically active (cf. DOS 21 17 293, 22 50 911, 23 04 764 and 24 23 679 ).

These phenylguanidines and also anthelminthica from the class of benzimidazole-2-carbamates, such as parbendazole, mebendazole, fenbendazole and other representatives of this substance class are poorly soluble in water and can therefore only be applied orally in humans

and veterinary medicine. With these substances, it is not possible to easily prepare parenterally applicable, locally well-tolerated solutions, as they are particularly required for the treatment of large animals such as cattle, horses and pigs.

Furthermore, according to DOS 26 30 847, methoxy-carbonylphenylguanidines are known with the formula:

wherein X means oxygen, sulfur, the -SO-, -SO^- or -CO group and

wherein X in position 4 or 5 is connected to the phenylguanidino residue, R means hydrogen, halogen, alkoxy-(C-^-C^) or trifluoromethyl, R^" means hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl,

2

optionally substituted aralkyl, R means hydrogen, alkyl, cycloalkyl, cycloalkylalkyl or aralkyl, whose salts with inorganic or organic acids are soluble in water and thus usable parenterally. They do indeed work against a broad spectrum of nematodes, but not sufficiently against liver leeches, a parasite that often occurs together with the nematode in the gastrointestinal tract, and is appropriately combated together with the nematodes.

According to DOS 24 41 201 and 24 41 202, it is true that benzimidazole carbamates with the formula

in which X means the group -OSO2- or -SO2O-, R means alkyl with 1 to 4 C atoms, R<1>and R" each independently means hydrogen, hydroxyl, alkyl or alkoxy with each time 1-4 C- atoms, halogen, trifluoromethyl or CN and which are effective against both nematodes and liver leeches, but due to the low solubility in water can only be applied orally.

The object of the invention is monocarboxylates of phenylguanidine sulfonic acid esters with the formula:

in which

X means -OS02- or -S020-

R means hydrogen, halogen, alkyl with 1-4 C atoms,

alkoxy with 1-4 C atoms, -CN or -CF.,,

R means hydrogen,

optionally substituted alkyl,

optionally substituted alkoxy,

optionally substituted alkoxyalkyl or

optionally substituted aralkyl and

2

R means hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl

or aralkyl, and their physiologically tolerable salts with organic or inorganic acids.

The compounds according to the invention with formula I have a basic character. They can be used as anthelmintic active substances, as free bases or in the form of their salts with physiologically tolerable inorganic or organic acids, for example hydrohalides, preferably hydrochlorides, sulphates, phosphates, nitrates, maleinates, fumarates, acetates, propionates, lactates, methanesulphonates or naphthalene disulfonates.

The object of the invention is also a process for producing monocarboxylates of phenylguanidine sulfonic acid esters with formula I, the process being characterized by

a) a substituted aniline derivative of formula II

in which X, R and R have the meaning given for formula I, are converted

either

a-^) with an isothiourea f derivative of formula III

2 3

in which R has the meaning given in formula I and R means alkyl with 1-4 C atoms, or

a2^ with an O-methylisourea derivative of formula IIIa

3

in which R means alkyl with 1-4 O atoms,

in the presence of a solvent and optionally in the presence of an acid, or

b) a phenylguanidine biscarboxylate of formula IV

. wherein X, R and R 1 have the above meaning and R 4 means

alkyl or alkoxy,

hydrolyzed,

and optionally a thus formed compound of formula I, in which R 2 means hydrogen is alkylated.

In the formulas I to IV, the substituents have the following preferred meanings: R as halogen means fluorine, chlorine or bromine, especially chlorine and fluorine.

Alkoxy-(C^-C^) means methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and t-butoxy, preferably methoxy and ethoxy.'

As optionally substituted alkyl R is linear or branched alkyl with preferably 1-6, especially 1-4 C atoms. For example, optionally substituted methyl, ethyl,

n- and i-propyl, n-,1- and t-butyl.

As optionally substituted alkoxy R"<*>" is straight or branched alkoxy with preferably 1 to 6, especially 1 to 4 C atoms. For example, any substituted methoxy must be removed. ethoxy, n- and i-propoxy and n-, i- and t-butoxy.

as optionally substituted alkoxyalkyl means straight or branched alkoxyalkyl with preferably 1-6, especially 1-4 C atoms in the alkoxy part and preferably 1-6, especially 1-4 C atoms in the alkyl part. For example, it must be mentioned if substituted

methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl.

R as optionally substituted aralkyl means optionally

in the aryl part and/or the alkyl part substituted aralkyl with preferably 6-10 carbon atoms in the aryl part and preferably 1-4, especially 1 or 2 carbon atoms in the alkyl part, the alkyl part can be

straight or branched. For example, optionally substituted benzyl and phenylethyl are mentioned.

The different residues R can have one or more, preferably 1-3, especially 1 or 2 identical or different substituents. As substituents, for example: Alkoxy with preferably 1-4, especially 1 or 2 carbon atoms such as methoxy, ethoxide, n- and i-propyloxy and n-, i- and t-butyloxy; alkylthio with preferably 1-4, especially 1 or 2 carbon atoms, such as methylthio, ethylthio, n- and i-propylthio and n-, i- and t-butylthio; haloalkyl with preferably 1-4, especially 1 or 2 carbon atoms and preferably 1-5, especially 1-3 halogen atoms, the halogen atoms being the same or different, and the halogen atoms are preferably fluorine, chlorine or bromine, especially fluorine as trifluoromethyl; hydroxy; halogen, preferably fluorine, chlorine, bromine and iodine, especially fluorine and chlorine; cyano; nitro; amino; mono-alkyl- and dialkylamino with preferably 1-4, especially 1 or 2 carbon atoms per alkyl group such as methylamino, methyl-ethyl-amino,

n- and i-propylamino and methyl-n-butylamino; carbalkoxy with preferably 2-4, especially 2 or carbon atoms, such as carbomethoxy and carboethoxy; sulfo (-SO^H); alkylsulfonyl with preferably 1-4, especially 1 or 2 carbon atoms, such as methylsulfonyl and ethylsulfoyl; arylsulfonyl with preferably 6 or 10 aryl carbon atoms such as phenylsulfonyl.

R 2 as alkyl means straight or branched alkyl with preferably 1-6, especially 1-4 carbon atoms. Examples include methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.

R 2 as cycloalkyl means mono-, bi- and tricyclic cycloalkyl with preferably 3-10, especially 3, 5 or 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and adamantyl.

Cycloalkylalkyl R 2 stands for cycloalkylalkyl with preferably 3-10, especially 3/5 or 6 carbon atoms in the cycloalkyl part and preferably 1-6, especially 1-4 carbon atoms in the alkyl part.

Examples include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl and cyclohexylethyl.

Aralkyl R stands for aralkyl with preferably 6 to 10, especially 6 carbon atoms in the aryl part and preferably 1-4, especially 1 or 2 carbon atoms in the alkyl part, the alkyl part can be straight-chained or branched. Examples include benzyl and phenylethyl.

As R3-alkyl-(C^-C^) in formula III are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, especially methyl and ethyl.

R 4 as alkyl means straight or branched alkyl with preferably 1-6, especially 1-4 carbon atoms. For example, mention should be made of methyl, ethyl, n- and i-propyl, n-, i- and t-butyl.

R as alkoxy means straight or branched alkoxy with . preferably 1-6, especially 1-4 carbon atoms. Examples include methyl, ethoxy, n- and i-propoxy and n-, i- and t-butoxy.

i Among the monocarboxylates of phenylguanidine sulfonic acid esters of formula I, those in which the substituents R means hydrogen, chlorine, trifluoromethyl or -CN, R"*" means hydrogen, methyl, ethyl, propyl, isopropyl or methoxymethyl have proven to be particularly suitable as anthelmintics and R<2> is hydrogen.

The substituted aniline derivatives of formula II and the phenylguanidine derivatives of formula IV used as starting materials, as well as the method for their preparation, are known from DOS 2608 238.

Isothioureas of formula III are partially known.

They can be obtained by reacting optionally substituted S-alkylisothioureas with chloroformic acid methyl ester.

In detail, for example, the following isothioureas with formula III should be mentioned: N-methoxycarbonyl-S-methyl-isothiourea

N-Methoxycarbonyl-N<1->methyl-S-methyl-isothiourea

N-methoxycarbonyl-N'-ethyl-S-methyl-isothiourea

N-methoxycarbonyl-N1-propyl-S-methyl-isothiourea N-methoxycarbonyl-N'-isopropyl-S-methyl-isothiourea.

N-methoxycarbonyl-N'-butyl-S-methyl-isothiourea

N-methoxycarbonyl-N'-isobutyl-S-methyl-isothiourea N-methoxycarbonyl-N'-tert-butyl-S-methyl-isothiourea N-methoxycarbonyl-N'-cyclohexyl-S-methyl-isothiourea

N-methoxycarbonyl-N'-cyclohexylmethyl-S-methyl-isothiourea N-methoxycarbonyl-N<1->benzyl-S-methyl-isothiourea

N-methoxycarbonyl-N'-α-phenethyl-S-methyl-isothiourea N-methoxycarbonyl-N'-3-phenethyl-S-methyl-isothiourea.

O-methylisoureas of formula Illa can be obtained by reaction, of. corresponding O-alkylisourea f is with chloroformic acid methyl ester.

Solvents are obtained by reacting compounds of formula II'' with> substances of formula III resp.

Harmful to all polar organic solvents, preferably

show alcohols, such as methanol, isopropanol, as well as their mixtures

with water, ketones, such as acetone, as well as their mixture with water, but also ethers such as dioxane or tetrahydrofuran.

In the preparation of the compounds of formula II from compounds of formula II with substances of formula III or Alternatively, desirable organic or inorganic acids can be used as catalysts. Preferably use readily available ones

acid such as hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, p-toluenesulfonic acid.

The reaction temperatures during production can vary

are within an area. Generally, one works between 0°C and 120°C, preferably between 10 and 30°C. The turnover is usually carried out at normal pressure.

The reaction of the compounds of formula II with such

with formula III or Illa conveniently takes place in equimolar amounts.

The hydrolyses of compounds of formula IV through

is conveniently conducted by heating in an alcohol such as methanol, ethanol, isopropanol and their mixtures with water in the presence of a base, e.g. an aliphatic amine such as methylamine, butylamine, piperidine or N-methyl-piperazine, an alcoholate such as sodium methylate, or in the presence of an inorganic base such as KOH or NaOH. Solutions of butylamine in methanol or ethanol have proven to be particularly suitable. The hydrolysis is also successful by prolonged heating with water in the presence of a solvent such as acetone.

The reaction temperatures of the hydrolysis reaction can be varied within a large range, usually working between 0°C and 120°C, preferably between 40 and 100°C. The turnover is usually carried out at normal pressure. It is usually in the basic range of

ended already after a few minutes.

The monocarboxylates of the phenylguanidine sulfonic acid esters of formula I include, for example, the following compounds: N-(2-acetamido-5-phenylsulfonyloxy-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-formamido-5-phenylsulfonyloxy-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-propionamido-5-phenylsulfonyloxy-phenyl)-N-methoxycarbonyl-guanidine

N-(2-butyramido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-guanidine N-(2-iso-butyramido-5-phenylsulfonyloxy-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-valeramido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-guanidine

.N-(2-iso-valeramido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-1-guanidine

N-(2-capronamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-iso-capronamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-guanidine-N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-acetamido-5-(4-chloro-phenylsulfonyloxy)-phenyl)-N N -methoxycarbonyl-guanidine

N-(-2-acetamido-5-(3-chloro-phenylsulfonyloxy)-phenyl)-N'-methoxy-carbonyl 1-guanidine

N-(2-acetamido-5-(2-chloro-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl 1-guanidine

N-(2-methoxyacetamido-5-(3-chloro-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-1-guanidine

N-(2-methoxyacetamido-5-(3-bromo-phenylsulfonyloxy)-phenyl)-N1 - methoxycarbonyl1-guanidine

N-(2-Methoxyacetamido-5-(3-methyl-phenylsulfonyloxy)-phenyl)-N*-methoxycarbonyl-1-guanidine

N-(2-methoxyacetamido-5-(3-methyl-phenylsylphonyloxy)-phenyl)-N'-methoxycarbonyl-1-guanidine

N-(2-methoxyacetamido-5-(3-tert-butyl-phenylsulfonyloxy)-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-methoxy-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-ethoxy-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-1-guanidine

N-(2-methoxyacetamido-5-(3-propoxy-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-isopropoxy-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-butoxy-phenylsulfonyloxy)-phenyl)-N1-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-isobutoxy-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(4-cyano-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-trifluoromethyl-phenylsulfonyloxy)-phenyl)-N<1->methoxycarbonyl-1-guanidine

N-(2-methoxyacetamido-5-(3-chloro-4-methyl-phenylsulfonyloxy)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-propionamido-5-(3-trifluoromethyl-phenylsulfonyloxy)-phenyl-N'-methoxycarbonyl-guanidine

N-(2-butyramido-5-(3-trifluoromethyl-phenylsulfonyloxy)-phenyl-N'-methoxycarbonyl-guanidine

N-(2-formamido-5-(3-trifluoromethyl-phenylsulfonyloxy)-phenyl-N'-methoxycarbonyl-guanidine

N-(2-Methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbo-ny 1-N"-methyl 1-guanidine

N-(2-Methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N<1->methoxycarbo-ny 1-N "-butyl 1-guanidine

N-(2-Methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N<1->methoxycarbo-ny 1-N"-cyclohexy 1-guanide in

N-(2-formamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-N"-methylguanidine

N-(2-propionamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-N"-methylguanidine

N-(2-butyramido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-N"-methylguanidine

N-(2-acetamido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-methylguanidine

N-(2-butyramido-5-phenoxysulfonyl-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-iso-butyramido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-valeramido-5-phenoxysulfonyl-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-iso-valeramido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-capronamido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-iso-capronamido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-Methoxyacetamido-5-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine N-(2-acetamido-5-(4-chloro-phenoxysulfonyl)-phenyl.)-N'-methoxycarbonyl-guanidine

N-(2-acetamido-5-(3-chloro-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-acetamido-5-(2-chloro-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-chloro-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-Methoxyacetamido-5-(3-bromo-phenoxysulfonyl)-phenyl)-N1-methoxy- .

carbonyl-guanidine

N-(2-methoxyacetamido-5-(3-methyl-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N, (2-methoxyacetamido-5-(3-tert-butyl-phenoxysulfonyl)-phenyl)-N1-me toxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-methoxy-phenoxysulfonyl)-phenyl)-N1-methoxycarbonyl-guanidine

N-(2-Methoxyacetamido-5-(3-ethoxy-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-propoxy-phenoxysulfonyl)-phenyl)-N1-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-isopropoxy-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-1-guanidine

N-(2-methoxyacetamido-5-(3-butoxy-phenoxysulfonyl)-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(3-isobutoxy-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-(4-cyano-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-Methoxyacetamido-5-(3-trifluoromethyl-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine N-(2-Methoxyacetamido-5-(3-chloro-4-methyl-phenoxysulfonyl)-phenyl)- N<1->methoxycarbonyl-guanidine

N-(2-propionamido-5-(3-trifluoromethyl-phenoxysulfonyl)-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-butyramido-5-(3-trifluoromethyl-phenoxysulfonyl)-phenyl)-N'-methoxycarbonyl-guanidine

N-(2-formamido-5-(3-trifluoromethyl-phenoxysulfonyl)-phenyl)-N<1->methoxycarbonyl-guanidine

N-(2-methoxyacetamido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-N"-methyl-guanidine

N-(2-methoxyacetamido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-N"-butyl-guanidine N-(2-methoxyacetamido-5-phenoxysulfonyl-phenyl)-N<1->methoxycarbonyl-N"-butyl -guanidiri

N-(2-methoxyacetamido-5-phenoxysulfonyl-phenyl)-N'-methoxycarbonyl-N"-dichlorohexyl-guanidine

N-(2-formamido-5-phenoxysulfonyl-phenyl)-N<1->methoxycarbonyl-N"-methyl-guanidine

N-(2-propionamido-5-phenoxysulfonyl-phenyl)-N<->methoxycarbonyl-N"-methyl-guanidine

N-(2-butyramido-5-phenoxysulfonyl-phenyl)-N<1->methoxycarbonyl-N"-methyl-guanidine.

The monocarboxylates of phenylguanidine sulfonic acid esters of formula I according to the invention are valuable chemotherapeutics and are suitable for combating parasitic diseases in humans and animals, especially helminths and liver leeches.

They are particularly effective against a large number of helminths, e.g. Haemonchus, Trichostrongylus, Ostertagia, Strongy-loides, Cooperia, Chabertia, Oesophagostomum, Hyostrongulus, Ankylostoma, Askaris and Heterakis and Fasciola. The effect is particularly pronounced against gastrointestinal strongylids and liver leeches, of which above all ruminants are attacked. Therefore, the compound according to the invention is used especially in veterinary preparations.

The compound according to the invention with formula I, unlike the compounds known according to DOS 21 17 293, 22 50 911, 23 04 764 and 24 23 679, can preferably be applied parenterally and works, unlike those known according to DOS 26 30 84 7 surprisingly effective against both nematodes and liver leeches.

The compound of formula I is administered, depending on the condition of the case, in dosages between 0.5 and .50 mg/kg body weight for 1 to 14 days.

For oral application, oral tablets, dragees, capsules, powders, granules or pastes are available which contain the active substances together with usual auxiliary or carrier substances such as starch, cellulose powders, talc, magnesium stearate, sugar, gelatin, calcium carbonate, finely divided silicic acid, carboxymethyl cellulose -loose or similar substances.

The process products are not only excellently effective when applied orally, but also work parenterally.

For parenteral application, either a compound of formula I is dissolved in an equivalent of an organic or inorganic acid, or a salt of these compounds is dissolved in water.

The possibility of parenteral application of compounds of formula I is a considerable advance in the anthelmintic treatment of animals, such as cattle, horses, pigs, sheep, dogs, cats, etc. It is particularly suitable for mass treatment of large animals such as cattle and horses, in particular, when these animals are simultaneously infected with liver leeches.

Manufacturing examples

Approach

Example 1. 1

A mixture of 3.4 g of 2-methoxyacetamido-5-phenylsulfonyloxy-aniline (formula II), 25 ml of methanol, 3 ml of glacial acetic acid and 2 g of N-methoxycarbonyl-S-methylisothiourea (formula III) is heated a day during reflux. After standing overnight at room temperature, the separated N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-methoxycarbonyl-guanidine (formula I) is filtered off. Yield 0.4 g, m.p. 19 0°C.

In an analogous way, from substituted 2-acylamino-aniline derivatives (formula II) and N-substituted N-methoxycarbonyl-S-methyl-isothioureas (formula III) you get: 1.2 N-(2-formamido-5-phenylsulfonyloxy-phenyl)- N'-methyl-N"-methoxycarbonyl-guanidine

1.3. N-(2-acetamido-5-phenylsulfonyloxy-phenyl)-N'-methyl-N"-methoxycarbonyl-guanidine

1.4 N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N<1->

methyl-N"-methoxycarbonyl-guanidine

1.5 N-(2-propionamido-5-phenylsulfonyloxy-phenyl)-N'-methyl-N"-methoxycarbonyl-guanidine

1.6 N-(2-Methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-ethyl-N"-methoxycarbonyl-guanidine

1.7. N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N\-propyl-N"-methoxycarbonyl-guanidine

1.8 N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-buty1-N"-methoxycarbonyl-guanidine

1.9<;>N-(2-Methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-isobuty1-N"-methoxycarbonyl1-guanidine

1.10 N-(2-Methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N<1->

cyclohexyl-N"-methoxycarbonyl-guanidine

1.11 N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-cyclohexylmethyl-N"-methoxycarbonyl-1-guanidine 1.12 N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-benzyl-N"-methoxycarbonyl -guanidine

Procedure a2)

Example 2

A mixture of 3.4 g of 2-methoxyacetamido-5-phenylsulfonyloxy-aniline (formula II), 2.5 ml of methanol, 3 ml of glacial acetic acid and 2 g of N-methoxycarbonyl-O-methylisourea (formula Illa) is heated. a day during reflux. After standing overnight at room temperature, the liquid is filtered off from the separated impurities, the filtrate is evaporated to dryness, the residue is taken up in vinegar, washed several times with water and the solvent is evaporated after drying with MgSO4 under reduced pressure. After stirring the residue with 0.5 n HCl at room temperature and precipitation of the filtrate with ammonia, the formed N-(2-methoxyacetamido-5-phenyloxy-phenyl)-N'-methoxycarbonyl-guanidine (formula I) is obtained in pure form. According to the thin-layer chromatography, it is identical to that according to Ex. 1 formed method-product.

Preparation of the starting material with formula Illa:

Dissolve 246 g of O-methylisourea sulfate in 300 ml of water and add dropwise at 10°C 163 ml of chloroformate methyl ester and then 170 g of NaOH, dissolved in 510 ml of water. Stir for a further 3 hours at room temperature. The reaction solution is then extracted with acetic acid and this extract is dried with anhydrous sodium sulphate. After evaporation under reduced pressure at a

maximum bath temperature of 40°C, N-methoxycarbonyl-O-methyl-isourea is obtained as an oil, which eventually solidifies into crystals with a melting point of 40°C. Yield 150 g.

Method b) (Hydrolysis)

Example 3

A mixture of 2 g of N-(2-methoxyacetamido-5-phenylsulfonyloxyphenyl)-N<1>,N"-bis-methoxycarbonylguanidine (formula IV), 20 ml of methanol and 2 ml of butylamine is stirred for 10 minutes at 50°C. Already after two minutes, a clear solution is formed, from which N-(2-methoxyacetamido-5-phenylsulfonyl-oxy-phenyl)-N1-methoxycarbonyl-guanidine (formula I) precipitates shortly afterwards. The reaction mixture is allowed to stand a few hours at 10° C., filter off the precipitate and wash it with methanol. Yield 1.7 g, m.p. 190° C. during cleavage. The process product is identical to that obtained according to Example 1.

The N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N'-N"-bis-methoxycarbonyl-guanidine (formula IV) required for carrying out the reaction is obtained according to. DOS 26 08 .238

Ex. 5.2.

Instead of butylamine, a 40% aqueous methylamine solution, piperidine or N-methyl-piperazine can also be used with the same working technique. Similar results are also obtained with caustic soda, ammonia or sodium methylate in alcoholic solution.

Example 4 (also method b) )

Analog Ex. 3, the compounds of formula I listed in the following table are prepared from the corresponding starting materials

4

with formula IV, in which X each time means -SO2O- and R -OCH^:

Example 5 (also method b))

Analog Ex. 3, the compounds of formula I listed in the following table are prepared from the corresponding starting materials of formula IV, in which X each time means -O-S09- and 4 z

R stands for -0CH3:

For the production of the process product according to Ex. 3.36 required N-(2-acetamido-5-(3-trifluoromethyl-phenylsulfonyloxy)-phenyl-N',N"-bis-methoxycarbonylguanidine (formula IV) with m.p. 152°C is obtained corresponding to Ex.■3-in DOS 26 08 238 of 2-nitro-4-(3-trifluoromethyl-phenoxysulfonyl)-chlorobenzene with m.p. 65°C over 2-nitro-4-(3-trifluoromethyl-phenoxysulfonyl)-aniline with m.p. 130°C, 2-nitro -4-(3-trifluoromethyl-phenoxysulfonyl)-aniline with a melting point of 130°C and 2-nitro-4-(3-trifluoromethyl-phenoxysulfonyl)-acetanilide with a melting point of 114°C, as well as 2-amino-4-(3 -trifluoromethyl-phenoxy-sulfonyl)-acetanilide with mp 141°C.

Example 6 (method b))

2.5 g of N-(2-methoxyacetamido-5-phenyl-sulfonyloxy-phenyl)-N',N"-bis-methoxycarbonylguanidine (formula IV) are heated

in 25 ml of acetone and 25 ml of water for 24 hours in an autoclave at 90°C.

After cooling, the crude product is filtered off. For purification, it is stirred several times in 25 ml of 0/5 n HC1 at room temperature, each time the undissolved material is filtered off and the filtrate is mixed with ammonia. After filtering and drying the residue, 0.5 g of pure N-(2-methoxy<y>acetamido-5-phen<y>lsulfon<y>oxy-phen<y>l)rN<1->methoxycarbonyl-guanidine is obtained with m.p. 190°C (during decomposition),

which is identical to the process product from Ex. 1.

Example 7 (Salt formation)

One stirs 24 g of it according to Ex. 1 formed free N-(2-methoxyacetamino-5-phenylsulfonyloxy-phenyl)-N<1->methoxycarbonyl-guanidine in 250 ml of methanol and makes it congo acid with alcoholic hydrogen chloride solution. The solution is then evaporated to dryness

hot under reduced pressure, the residue is mixed with ether and hydrochloric

of N-(2-methoxyacetamido-5-phenylsulfonyloxy-phenyl)-N1-methoxycarbonyl-guanidine is filtered off. After washing with ether and drying under reduced pressure over caustic soda, the yield is 25 g.

Analogously, the hydrochlorides are obtained from the other process products as described in Ex. 2-6.

Claims (5)

1. Monocarboxylates of phenylguanidine sulfonic acid esters of formula I in which X means -OS02- or -S02 0-R means hydrogen, halogen, alkyl with 1-4 C atoms, alkoxy with 1-4 C atoms, -CN or -CF.,, 1 R means hydrogen, ► optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl. or optionally, substituted aralkyl and R 2 means hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl or aralkyl, and their physiologically tolerable salts with organic or inorganic acids. 2. Process for the production of monocarboxylates of phenylguanidine sulfonic acid esters of formula I, according to claim 1, characterized by ata) a substituted aniline derivative of formula II in which X, R and R"<*>" have the meaning given under formula I, either ^) is reacted with an isothiourea derivative of formula III in which R 2 has the meaning given under formula I and R 3 means alkyl with 1-4 C atoms, or a2 ) with an O-methylisourea derivative of formula Illa wherein R means alkyl with 1-4 C atoms, in the presence of a solvent and optionally in the presence of an acid, or b) a phenylguanidine bis-carboxylate of formula IV in which X, R and R 1 have the above meaning and R 1 means alkyl or alkoxy, i is hydrolysed, and optionally a thus formed compound of formula I, in which R 2 means hydrogen, is alkylated. 3. Medicinal product characterized by a content of a compound of formula I according to claim 1, in the mixture medium pharmaceutical common carrier and/or excipient. 4. i Use of a compound of formula I according to claim 1 for combating helminths in organs attacked thereby. 5. Monocarboxylates of phenylguanidine sulfonic acid esters with formula I in claim 1, wherein X means -S02 0- R means meta-trifluoromethyl R''" means methyl, ethyl, propyl or methoxymethyl and R 1 means hydrogen.